Abstract
Background
Pulmonary mucormycosis, a life-threatening infection of immunocompromised individuals, can have a 95% mortality rate, even with treatment. Intravenous (IV) liposomal amphotericin B (AmBisomeâ, AmBi) is used to treat the infection, but rapid growth of the pathogen can limit the drug’s effectiveness. In the present study we investigated whether nebulized (nebz) AmBi could improve treatment outcome using a neutropenic murine model of pulmonary mucormycosis.
Methods
Rhizopus oryzae (ATCC MYA4621) was grown on Potato Dextrose Agar for 3–7 days, followed by spore harvesting, and determination of spore viability. Male ICR mice were immunosuppressed with 200 mg/kg of cyclophosphamide d-2, d0, d+2, d+4, and d0 challenged intranasally with 1 × 106 spores. In Study 1, mice (n = 16 mice/gp) were given AmBi at 7.5 or 10 mg/kg IV for 6 days, or nebz AmBi for 20 minutes (1.33 mg/mL AmBi in reservoir) for 4 days. In Study 2, 16 mice/gp were given AmBi at 15 mg/kg IV for 6 days or nebz AmBi for 7 days. PBS was the control. Lungs and kidneys were collected d+6 to determine drug concentration by a bioassay (n = 7–8 mice/gp) and morbidity (n = 8 mice/gp) monitored to d+21.
Results
In Study 1, survival was significantly better with nebz AmBi for 4 days (50%) or 10 mg/kg IV AmBi (33%) vs. 7.5 mg/kg IV AmBi (0%) (P < 0.003). In Study 2 with 13% survival in the PBS mice, 7 days of nebz AmBi produced 100% survival and 15 mg/kg IV AmBi gave 83% survival (P < 0.02 vs. PBS), underscoring the need for more intensive treatments. In Study 2, we also observed that average lung drug levels with nebz AmBi were significantly lower (3 μg/g lung) than with 15mg/kg AmBi IV (19 μg/g lung) (P = 0.003), even though both treatments were comparably effective. Kidney drug levels with 15 mg/kg AmBi IV were 13 μg/g and in comparison, nebz AmBi produced no detectable drug.
Conclusion
Daily nebulization of AmBi for one week or a high dose of IV AmBi at 15 mg/kg for 6 days protected the mice from severe pulmonary mucormycosis caused by R. oryzae, delivering effective drug levels to the lungs. The IV treatment yielded elevated levels of drug in the kidneys, while nebulization with AmBi produced no detectable drug in the kidneys. This indicated that nebz AmBi would be a less nephrotoxic, but still very effective route for drug delivery.
Disclosures
All authors: No reported disclosures.
Session: 162. PK/PD and Susceptibility Testing
Friday, October 4, 2019: 12:15 PM